Method of Treating Dyskinesia

ABSTRACT

Methods of treating patients with dyskinesias, by administering a therapeutically effective amount of a dual-action mu-opioid receptor antagonist/kappa-opioid receptor agonist or prodrug thereof to a subject in need thereof, sufficient to mitigate the dyskinesia. Alternatively, a combination of both a mu-opioid receptor antagonist or prodrug thereof, and a kappa-opioid receptor agonist or prodrug thereof can be administered, either together or separately.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority under 35 U.S.C.§119(e) of U.S. Provisional Application Ser. No. 61/480,415, filed onApr. 29, 2011, the entire disclosure of which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to a method of treatment for dyskinesias,including levodopa-induced dyskinesias (LID) in Parkinson's disease, andthe dyskinesias associated with Tourette's syndrome, tardive dyskinesiaand Huntington's disease.

BACKGROUND OF THE INVENTION

Parkinson's disease (PD) is the second most common neurodegenerativedisorder afflicting 1.5 million individuals in the US and 6.3 millionworldwide. The incidence of PD is expected to double by the year 2040.In the US, 50,000 new cases are diagnosed per year, and 1% of thepopulation over the age of 55 is afflicted. The annual societal cost ofPD is above $25 billion in the US alone.

The most common treatment for PD is 3,4-dihydroxyphenylalanine (levodopaor L-DOPA). While it remains the most effective therapy for the motordisability caused by PD, the vast majority of patients suffering from PDeventually develop a side effect characterized by abnormal involuntarymovements known as L-DOPA induced dyskinesias (LID), which substantiallycompounds patient disability. Thus, LID is a common, devastatingcomplication of the most efficacious therapeutic agent for PD.Dyskinesia is a disorder characterized by the presence of involuntarymovements that are often uncontrollable. These movements are oftenchoreiform (dance-like) in appearance but can also be more jerky andabrupt. They can affect any body parts including the arms and legs,muscles of the torso, chest, pelvis, face, lips, tongue, eyelids, andneck. It can even affect respiratory muscles. Some of these movementscan be strong and violent that can lead to injuries including to thecervical spine (neck). Thus, dyskinesia is a major source of disability.Therefore, although L-DOPA is the gold standard in the management of PD,long-term treatment with L-DOPA is problematic. L-DOPA-induceddyskinesia affects 50% of treated PD patients by 5 years, and >90% by 10years, which translates to an increase of approximately 10% per year.There are approximately 200,000 cases of LID in the US alone. Currently,amantadine (1-adamantanamine hydrochloride) is the only drug availablethat can modestly reduce LID, representing a deficient treatment withsignificant side effects of its own. Amantadine has an anti-dyskineticeffect likely due to its NMDA glutamate receptor antagonism, and itremains the only marketed agent with such a property. Several otherexperimental compounds targeting various transmitter systems have beentested, all with negative clinical trial outcomes. Moreover, in PDpatients, LID is the main indication for the invasive and costly brainsurgery known as Deep Brain Stimulation (DBS), an extreme option withthe potential for serious neuropsychiatric side effects as well as theusual risks associated with invasive brain surgery. As a result, manypatients are deemed poor candidates for this surgery, leaving their LIDinadequately controlled.

Opioid Receptors and LID

Central to the development of LID appear to be changes in neuronalnetworks that are modulated by glutamatergic, adenosinergic, adrenergic,dopaminergic, serotoninergic, endocannabinoid and opioid mediatedneurotransmission, all of which have been characterized to be altered indisease. Of these, opioid receptor mediated neurotransmission is ofparticular interest as opioids are co-transmitters that modulate basalganglia function. Through this action, opioid drugs may help blunt thenegative effects of pulsatile stimulation with L-DOPA therapy that ispathogenically related to LID. In LID, precursors of endogenous opioidreceptor ligands are massively upregulated, with preproenkephalin levelsincreased in the striatum in animal models, as well as being observed inpostmortem studies of patients. Additionally, enkephalin, dynorphin andalpha-neoendorphin are elevated significantly in the dyskinetic state,but not in normal or nondyskinetic Parkinsonian state. Therefore, it hasbeen proposed that opioid receptor antagonism may be of benefit.However, the complexity of the basal ganglia circuitry, the presence ofopioid receptors both pre- and post-synaptically, and on both excitatoryand inhibitory neurons, significantly compound the intricacies of theresponse to opioid receptor ligands that must be considered. There arethree major relevant classes of opioid receptors with differentialdistributions in the basal ganglia and with different functions:

-   -   Delta (δ)—Expressed predominantly in striatum and subthalamic        nucleus, with lower levels in Globus Pallidus (GP) segments.        These receptors regulate glutamate and acetylcholine release in        the striatum.    -   Kappa (κ)—Expressed in all basal ganglia regions (striatum, GPe,        GPi, STN, SN) & thalamus.    -   Mu (μ)—Expressed in all basal ganglia regions and thalamus.        Further complexity arises as expression of opioid receptors        change in the Parkinsonian state. For example, kappa receptors        are decreased in substantia nigra, and kappa and mu receptors        are decreased in GPi in LID, likely secondary to alterations in        opioid ligand expression. This complexity in distribution and        function is probably the reason why non-selective antagonists        have shown extremely varied efficacy in LID, worsening, not        affecting, or ameliorating symptoms in animal models, and have        not been effective in small clinical trials. Therefore, a level        of specificity is believed to be required, but the precise        nature of this specificity appears to be complex. The effects of        more compounds can be summarized as follows:    -   The μ-opioid receptor selective antagonist cyprodime        significantly reduces peak-dose LID. However, the selective        μ-opioid receptor antagonist ADL5510 reduces LID but with a        U-shaped dose response curve    -   The κ-opioid receptor selective agonist U50,488 reduces LID but        worsens parkinsonism in MPTP-treated primates. However, the        κ-opioid receptor selective antagonist nor-BNI moderates        levodopa-induced hyperkinesias in the 6-hydroxydopamine-lesioned        rat model.    -   Lower doses of the selective δ-opioid receptor antagonist        naltrindole reduce levodopa-induced rotations in        hemiparkinsonian marmoset monkeys.    -   Morphine (nonselective opioid receptor agonist) reduces        dyskinetic movements in Parkinsonian primates and patients    -   Naloxone and Naltrexone (nonselective opioid receptor        antagonists) have been tested with variable effects in monkeys        and humans reporting no change, increases or decreases in LID.

Collectively, the compounds tested to date indicate potential formodulating opioid receptors, but also indicate great complexity. Eventhose that are efficacious at some doses may display U-shaped doseresponse curves as non-specificity becomes an issue such as occurs withADL5510. Consideration of these studies indicates that the mostefficacious anti-dyskinetic agent acting on the opioid receptor systemwould have an as yet undiscovered mixture of pharmacological actions ondifferent opioid receptors.

Safety Considerations of Opioid Drugs

Activation of opioid receptors is achieved by a number of widely usedand abused opiates such as morphine and codeine. Despite the clearbeneficial effects that these compounds can have in analgesia and otherindications, they can have severe addictive and sedative effects, whileantagonists can precipitate withdrawal symptoms in patients on opiates.Therefore, doses relevant for LID need to be considered in light ofthese side effects. The major specific side effects relevant tomu-antagonists are related to the gastrointestinal tract and dysphoria,while for kappa-agonists are sedation, worsening parkinsonism anddysphoria for example.

In summary, in LID there are increases in the release of opioid peptideprecursors, therefore, modulation of opioid receptors is an attractivetherapeutic approach. The complexity of how different opioid receptorsregulate signaling at different sites within the circuitry of the basalganglia dictates the selectivity profile that will be efficacious tomodulate. The broad spectrum opioid receptor antagonists, such asNaloxone and Naltrexone, have been proposed as possible therapeutics,but have not been clinically successful. Selective agents for specificopioid receptor isoforms may offer limited benefits, but alsodemonstrate opposing dose-dependent effects that can substantiallyreduce their utility with significant dose-limiting adverse effects.

Thus, there remains a significant need for a therapeutic agent to treatL-DOPA-induced dyskinesias, since LID is a critical condition affectinga large and increasing population of PD patients. Further, there areother orphan diseases that exhibit dyskinesias for which treatments areunavailable or inadequate; these diseases include Huntington's disease,Tourette's syndrome and tardive dyskinesia. The present inventionaddresses these unmet needs.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to a novel use of Nalbuphine and relatedcompounds as a therapeutic agent to treat dyskinesias, especially L-DOPAinduced dyskinesias (LID), common in PD patients. Specifically, thepresent invention comprises the use of Nalbuphine in the treatment ofLID.

In one embodiment, the present invention relates to methods of treatingor mitigating various forms of dyskinesia, including, but not limitedto, LID, especially in PD patients; tardive dyskinesias; Tourette'ssyndrome; and Huntington's disease, comprising administering atherapeutically effective amount of a dual-action mu-opioid receptorantagonist/kappa-opioid receptor agonist to a patient in need thereofsufficient to mitigate the dyskinesia. Mitigation of dyskinesia isdefined as reduced severity and/or duration of abnormal involuntarymovements based on validated scales administrated by trained personneland by patient diaries marking “on with non-troublesome dyskinesia” or“on with troublesome dyskinesia.” The dual-acting agents can be selectedfrom the group consisting of Nalbuphine, Nalorphine, Pentazocine,Butorphanol and combinations of two or more thereof, their prodrugs orrelated compounds. Preferably the dual-acting agent comprisesNalbuphine.

Another embodiment of the invention comprises administering atherapeutically effective amount of Nalbuphine to a subject in needthereof in a non-injectable composition comprising:

-   -   a. Nalbuphine in the form of a free-base or a pharmaceutically        acceptable derivative, prodrug or salt, in an amount of at least        0.01 milligram; and    -   b. a pharmaceutically acceptable carrier;        where the composition is in tablet or capsule form. Preferably        the Nalbuphine composition is administered orally. Preferably        component a. is present in an amount of at least 0.1 mg.

In yet another embodiment of the invention, the dual-actionmu-antagonist/kappa-agonist comprises Nalbuphine administered to asubject via a continuous infusion. Preferably the continuous infusiondose is at least about 0.0001 mg/kg/day.

Another embodiment of the invention is directed to a method of treatingor mitigating a dyskinesia, comprising administering therapeuticallyeffective amounts of both a mu-opioid receptor antagonist and akappa-opioid receptor agonist to a subject in need thereof, sufficientto mitigate said dyskinesia. The agents may be administered together orseparately.

A further embodiment of the invention is directed to a method oftreating or mitigating a dyskinesia, comprising administering atherapeutically effective amount of a prodrug of a dual-action mu-opioidreceptor antagonist/kappa-opioid receptor agonist to a subject in needthereof, sufficient to mitigate said dyskinesia. Preferably, the prodrugis a prodrug of Nalbuphine, most preferably an ester of Nalbuphine,optionally as a pharmaceutically acceptable salt.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 displays graphs of dyskinesia score over time for twoParkinsonian monkeys treated with L-DOPA with and without Nalbuphine.

FIG. 2 displays a graph of dyskinesia score over time for threeadditional Parkinsonian monkeys treated with L-DOPA with and withoutNalbuphine.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Nalbuphine—a DualMu-Antagonist/Kappa-Agonist

Nalbuphine (Nubain) is a synthetic opioid with activity as both amu-opioid receptor antagonist and a kappa-opioid receptor agonist. Ithas been used clinically since 1979 as an analgesic for moderate/severepain including for women in labor. It is the only narcotic of its typethat is not regulated under the Controlled Substances Act, an indicationof its safety, with the major side effect being mild sedation atanalgesic doses in a subset of people. According to our analysis,Nalbuphine has properties required to be an effective agent for LID witha safety window that makes its use viable at sub-analgesic, non-sedativedoses. It exhibits activity as a dual mu-opioid receptor antagonist andkappa-opioid receptor agonist. As such, it provides the opportunity tocombine these two activities into a single, safe, therapeutic agent.Thus, Nalbuphine offers key pharmacological advantages such as fixedratio of mu-antagonism/kappa agonism in relevant brain compartments,regardless of dose, dosage form or stage of the disease in a particularpatient. This unique characteristic results in a medicaladvantage—ability to treat LID without risk of exposing a patient toexcessive kappa agonism which has been reported to cause severe sideeffects in LID patients and other relevant disease states.

Another surprising finding is that kappa agonism of Nalbuphine exertsits anti-LID efficacy without worsening parkinsonism.

Currently, Nalbuphine is administered for pain relief as anintramuscular injection, which is not necessarily a desirable route forchronic administration in LID or other chronic conditions. Due to itssafety and efficacy, oral forms may be preferable. Oral formulations ofNalbuphine are disclosed in the following patents or patentpublications: U.S. Pat. No. 6,703,398; US 2009/0030026; EP 2402005; WO2007/127683 and US 2009/0060871. Although these have been provenefficacious, they are not commercially viable in the field of analgesiaand, thus, their further development and marketing has not beenachieved. We have generated proof-of-concept data with the injectabledosage form in the primate model of PD with LID.

One embodiment of the present invention relates to the novel use ofdual-action mu-opioid receptor antagonist/kappa-opioid receptoragonists, represented by Nalbuphine and related compounds, as atherapeutic agent to treat dyskinesia, especially L-DOPA induceddyskinesias (LID) common in PD patients. It is known that opioidtransmission in the basal ganglia is an integral part of voluntarymovement control; thus, this mechanism has been implicated in LID.Although modulation of specific opioid receptors has been proposed as atreatment for LID, the experimental agents examined to date haveresulted in clinical inefficacy and unacceptable side effects. Thus, oneparticular embodiment of the present invention is directed to the use ofa dual-action mu-opioid receptor antagonist/kappa-opioid receptoragonist agent, preferably Nalbuphine, in the treatment of LID anddyskinesias associated with other diseases such as tardive dyskinesias,Tourette's syndrome and Huntington's disease. Further, the invention isalso directed to the treatment of such dyskinesias with a combination ofboth a mu-opioid receptor antagonist and a kappa-opioid receptoragonist. This combination of drugs may be administered together orseparately. If administered separately, various time delays between theadministration of the individual dosage forms are possible, depending onthe needs of the patient. If administered together, a combination ofindividual dosage forms may be given, or the drugs may be formulated asa single composition.

One embodiment of the present invention offers a novel method oftreatment of LID and other dyskinesias using such dual-acting mu-opioidreceptor antagonist/kappa-opioid receptor agonist agents, which have theadvantages of possessing a low incidence of side effects, a “ceiling”for side effects, and being non-addictive. Furthermore, such dual-actingtherapeutic agents have surprisingly increased efficacy compared toother strategies and address an area of medicine with major, unmetneeds, vide infra.

In another embodiment, the present invention is directed to a method oftreating or mitigating various types of dyskinesias, including, but notlimited to, LID, especially in PD patients; tardive dyskinesias;Tourette's syndrome; and Huntington's disease and related diseases,comprising administering a composition comprising both a mu-opioidreceptor antagonist and a kappa-opioid receptor agonist.

In another embodiment, the present invention is directed to a method oftreating or mitigating various types of dyskinesias, including, but notlimited to LID, especially in PD patients; tardive dyskinesias;Tourette's syndrome; and Huntington's disease and related diseases,comprising administering a composition comprising a single therapeuticagent which is active both as a mu-opioid receptor antagonist and akappa-opioid receptor agonist. Representative of such dual-actingmu-opioid receptor antagonist/kappa-opioid receptor agonist agents isthe synthetic analgesic opioid, Nalbuphine.

In another embodiment, the present invention is directed to a method oftreating or mitigating dyskinesias comprising administering Nalbuphine,Nalorphine, Pentazocine, Butorphanol or a combination of two or more ofthese.

In a more specific embodiment, the present invention is directed to amethod of treating or mitigating various types of dyskinesias in apatient in need thereof, including, but not limited to LID, especiallyin PD patients; tardive dyskinesias; Tourette's syndrome; andHuntington's disease, comprising administering a safe and effectiveamount of Nalbuphine, preferably in the dosage range of about 0.001mg/kg to about 3 mg/kg.

In another embodiment, the present invention is directed to a method oftreating or mitigating dyskinesias comprising administering to a subjectin need thereof a non-injectable or injectable pharmaceuticalcomposition comprising a combination of both a mu-opioid receptorantagonist and a kappa-opioid receptor agonist, or alternatively,comprising a dual-acting therapeutic agent possessing both mu-opioidreceptor antagonist and kappa-opioid receptor agonist activities, invarious administration vehicles, including but not limited to tablets,capsules, caplets, syrups, gels, suppositories, inhalable powders,inhalable aerosols, sublingual sprays, sublingual solid dosage form,patch, intranasal sprays, intranasal aerosols, injectable solutions andinjectable suspensions including those delivered via minipumps and otherdevises capable of continuous delivery of the agent. If thepharmaceutical composition is administered by injection, the injectionmay be intravenous, subcutaneous, intramuscular, intraperitoneal or byother means known in the art. The present invention may be formulated byany means known in the art, including but not limited to formulation assuspensions, powders, lyophilized preparations, ocular drops, skinpatches, oral soluble formulations, sprays, aerosols and the like, andmay be mixed and formulated with buffers, binders, excipients,stabilizers, anti-oxidants and other agents known in the art.Administration means may include administration through mucousmembranes, buccal administration, oral administration, dermaladministration, inhalation administration, nasal administration and thelike.

In a preferred embodiment, the present invention is directed to a methodof treating or mitigating dyskinesias comprising administering to asubject in need thereof a non-injectable, pharmaceutically acceptableoral formulation comprising an active component including freebaseNalbuphine or a pharmaceutically acceptable derivative or salt ofNalbuphine, and a pharmaceutically acceptable carrier or adjuvant; andwherein the formulation is in tablet or capsule form. For the presentinvention, the term “derivative” means a compound derived from a drugmolecule, for example Nalbuphine, which can regenerate or release theparent drug (e.g, Nalbuphine) at a target site in vivo, for example whenacted upon by hydrolytic and/or oxidative enzymes. Such derivatives areknown as “prodrugs” in the medicinal chemistry arts. Prodrugs aregenerally derivatives of the drug, for example esters of carboxylicacids, or conjugates with amino acids, peptides or proteins. Prodrugderivatives influence the uptake, transport, toxicity and/or metabolismproperties of the parent drug.

There are known Nalbuphine prodrugs designed to improve itspharmacokinetic and pharmacodynamic profiles. For example, Nalbuphinecan be modified at the phenolic hydroxyl by acylation to form esters orby alkylation to form ethers. Furthermore, Nalbuphine can be coupled toan amino acid or short peptide. Also, Nalbuphine can be modified withdicarboxylic acids themselves or dicarboxylic acid linked-amino acids ordicarboxylic acid linked-peptides. Further, Nalbuphine can be modifiedwith a carbamate-linked amino acid or peptide. Nalbuphine can be furthermodified on its nitrogen atom by forming salts or N-oxides. As discussedabove, Nalbuphine can be converted to ester prodrugs which increase itsbioavailability. More specifically, formulation to increase Nalbuphine'sbioavailability can include vegetable oils, a cosolvent, and aneffective amount of a Nalbuphine ester prodrug or a pharmaceuticallyacceptable salt thereof, which can increase the oral bioavailability ofNalbuphine by more than 12 times, and prolong the retention time ofNalbuphine in the body, thereby maintaining a longer analgesic period,as well as reducing the analgesic cost, since Nalbuphine esters havelong-acting analgesic action. For example, the bioavailability ofsebacoyl di-Nalbuphine ester is improved over that of Nalbuphine itself.Nalbuphine prodrugs also include Nalbuphine covalently linked to anotherpharmaceutical agent, for example via an amino acid. For example,Nalbuphine can be converted into a 3-acetylsalicylate (aspirin)derivative. Such duplex prodrugs including Nalbuphine provide asignificant increase in the transdermal flux of drugs across human skin.Transdermal delivery of Nalbuphine and Nalbuphine pivalate fromhydrogels by passive diffusion and iontophoresis (vide infra) has alsobeen described. Therapeutic polymers such as polyesters and poly-amidesincorporating Nalbuphine, as well as poly-Nalbuphine derivatives canalso be prepared. Controlled release of Nalbuphine prodrugs frombiodegradable polymeric matrixes is influenced by prodrug hydrophilicityand polymer composition.

Pharmacokinetic and pharmacodynamic properties of Nalbuphine, itspharmaceutically acceptable salts, esters or other prodrugs can befurther modulated by various delivery systems. For example,biodegradable polymeric microspheres for Nalbuphine prodrug controlleddelivery have been described. Further, iontophoresis and electroporationenhance the transdermal delivery of Nalbuphine (NA) and two prodrugs,Nalbuphine benzoate (NAB) and sebacoyl di-Nalbuphine ester (SDN), whenapplied topically as solutions or hydrogels. Mucoadhesive buccal disksalso provide for novel Nalbuphine prodrug controlled delivery.

In a further embodiment of the present invention, prodrugs of mu-opioidreceptor antagonists and/or kappa-opioid receptor agonists and/or otherdual-action mu-antagonist/kappa-agonist compounds, and/or othertherapeutic agents can be used either as individual therapeutic agentsor in combination with any of the above for the treatment ofdyskinesias.

The present invention represents a novel treatment option for thosesuffering from LID as well as other forms of dyskinesias includingtardive dyskinesia, Huntington's chorea and Tourette's syndrome.Nalbuphine functions by modulating locomotion by interacting withmu-opioid receptor as an antagonist and kappa-opioid receptor as anagonist. Nalbuphine administration offers a distinct advantage in thatit does not cause significant euphoric, dysphoric or sedative effects,at the doses of the present invention. Additionally, the method of thepresent invention does not impair cognition or respiration, Furthermore,Nalbuphine has been shown to be safe (in 30 years of clinical use as ananalgesic), non-addictive at sub-analgesic doses, and having a “ceilingeffect” that limits adverse effects at higher doses.

The compounds described herein can also be co-administered with otheranti-dyskinetic drugs (e.g. amantadine, adenosine A2a antagonists,alpha-2 adrenergic antagonists (e.g. fipamezole)) and/or anti-Parkinsontreatments (e.g. L-DOPA, dopamine agonists, monoamine oxidase (MAO)inhibitors (e.g. Safinamide), catechol-O-methyl transferase inhibitors,deep brain stimulation, etc.). Thus, a further embodiment of theinvention encompasses a method of treating or mitigating a dyskinesiawherein a dual-action mu-antagonist/kappa-agonist or prodrug thereof isadministered with another anti-Parkinson agent. Preferably the otheranti-Parkinson agent is selected from the group consisting of L-DOPA,dopamine agonists, MAO inhibitors, COMT inhibitors, amantadine andanti-cholinergics. More preferably the other anti-Parkinson agentcomprises L-DOPA. Most preferably the other anti-Parkinson agent isL-DOPA. Most preferably the dual-action mu-antagonist/kappa-agonist isNalbuphine or a prodrug thereof, and the other anti-Parkinson agent isL-DOPA. Administration of either of the agents can be delayed by 0-12hrs, preferably by 0-6 hours, and administration can be via the same orby a different route.

EXAMPLES

The present invention is described more fully by way of the followingnon-limiting examples. Modifications of these examples will be apparentto those skilled in the art. In order to target Nalbuphine for thetreatment of Levodopa-induced dyskinesias, a major need for Parkinson'sdisease patients, its activity is confirmed in preclinical models andthose data are used to guide dosing for human clinical trials.

Example 1 Assess Efficacy, Safety and Dosing of Nalbuphine in a PrimateModel of L-DOPA Induced Dyskinesias

Studies in primates are necessary to closely replicate the humancondition and are used to fine tune the dosing and efficacy prior to ahuman clinical trial, The primate model of Parkinson's disease is a wellestablished model that replicates the motor manifestations of the humandisease, is responsive to PD therapeutics, and develops L-dopa-induceddyskinesia. Macaque monkeys (Macaca Fascicularis) are used in thesestudies, to which MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;0.5-0.8 mg/kg) is administered intravenously (iv) until a stableParkinsonian state of moderate to severe degree develops. The animalsare then administered oral levodopa/carbidopa (Sinemet 25/100) twicedaily until stable dyskinesias are established. The response of animalsto subcutaneous (SC) injections of levodopa methyl ester alone is thenassessed, and the optimal dose established for each animal that resultsin moderate and reproducible dyskinesia. Levodopa methyl ester isroutinely given with benserazide, a decarboxylase inhibitor to lessenthe peripheral side effects of levodopa. Animals are then administeredNalbuphine SC, along with levodopa methyl ester plus benserazide toassess the effect of the combination on the severity and duration ofdyskinesias. A minimum of 4 Nalbuphine doses and vehicle areadministered in random order to ensure integrity of the studies, withthe aim of finding a minimum efficacious dose and determining a viabledosing strategy for a future clinical trial. Each test dose includingthe vehicle is repeated 3 times. Monkeys are scored before L-DOPAadministration and every 20 min interval thereafter for 3-4 hours. Testsare performed by trained observers in the morning after overnightfasting and repeated at intervals of at least 48 hr for drug washout. Inaddition to general clinical evaluation, a standardized scale forMPTP-treated primates to assess dyskinesias, the Klüver board test(motor task), and a scale assessing the nervous system (particularlyalertness) is used. The examples described above identify efficaciousdoses of Nalbuphine that can be translated to human clinical trials.

Data

Macaques received iv MPTP to induce advanced Parkinsonism and weretreated with chronic oral L-dopa/carbidopa to induce dyskinesia.

Example 1A

Nalbuphine was tested in two Parkinsonian monkeys with LID, at 0.1 mg/kgand 0.2 mg/kg given with 75 mg levodopa methyl ester (plus benserazide)all injected SC. Responses were evaluated with a motor disability scalefor Parkinsonian monkeys including abnormal involuntary movements(PD-MDS). In both animals, dyskinesia severity was ameliorated andlasted for a shorter time when Nalbuphine was co-administered comparedwith levodopa administration alone (FIG. 1). No sedation occurred atthese doses.

Example 1B

Three Parkinsonian monkeys with LID were tested. Animals were challengedwith 75 mg SC injection of L-dopa methyl ester (plus benserazide) aloneor immediately following SC Nalbuphine (0.25 mg/kg or 0.5 mg/kg), andresponses were evaluated with a motor disability scale for Parkinsonianmonkeys including abnormal involuntary movements. Each treatment wastested 2-3 times per animal. Error bars=S.E.M. Substantial reduction inthe severity and duration of dyskinesias were noted with Nalbuphineco-administration. The effect of 0.5 mg/kg was slightly more pronouncedthan 0.25 mg/kg suggesting a dose-response effect (FIG. 2). Again, nosedation or other adverse effects were noted in these animals.

The foregoing examples and descriptions of the preferred embodiments arepresented as illustrating, rather than as limiting the present inventionas defined by the following claims. The present invention encompassesall variations and combinations of the features presented above, and areintended to be within the scope of the claims.

1. A method of treating or mitigating a dyskinesia, comprisingadministering a therapeutically effective amount of a dual-actionmu-opioid receptor antagonist/kappa-opioid receptor agonist to a subjectin need thereof, sufficient to mitigate said dyskinesia.
 2. The methodof claim 1 wherein said dual-action mu-antagonist/kappa-agonist isselected from the group consisting of Nalbuphine, Nalorphine,Pentazocine, Butorphanol and combinations of two or more thereof.
 3. Themethod of claim 1 wherein said dual-action mu-antagonist/kappa-agonistcomprises Nalbuphine, administered to a subject at a dose between 0.001mg/kg and 3 mg/kg.
 4. The method of claim 1 wherein said dual-actionmu-antagonist/kappa-agonist comprises Nalbuphine, administered to asubject in a non-injectable composition comprising: a. an activecomponent including Nalbuphine in the form of a free-base or apharmaceutically acceptable derivative, prodrug or salt, in an amount ofat least 0.01 mg; and b. a pharmaceutically acceptable carrier; whereinsaid composition is in tablet or capsule form.
 5. The method of claim 1wherein said dual-action mu-antagonist/kappa-agonist comprisesNalbuphine, administered to said subject in a non-injectablepharmaceutical composition for treating Parkinson-associated dyskinesia,wherein said pharmaceutical composition is in a form selected from thegroup consisting of tablets, capsules, syrups, gels, suppositories, skinpatches, inhalable powders, inhalable aerosols, sublingual sprays orsublingual solid dosage form, intranasal sprays and intranasal aerosolsor through a medical device capable of continuous delivery of apharmaceutical agent.
 6. The method of claim 1 wherein said dyskinesiais levodopa-induced, in a subject diagnosed with Parkinson's disease. 7.The method of claim 1 wherein said dyskinesia is in a subject diagnosedwith tardive dyskinesia.
 8. The method of claim 1 wherein saiddyskinesia is in a subject diagnosed with Tourette's syndrome.
 9. Themethod of claim 1 wherein said dyskinesia is in a subject diagnosed withHuntington's disease.
 10. A method of treating or mitigating adyskinesia, comprising administering therapeutically effective amountsof both a mu-opioid receptor antagonist or prodrug thereof, and akappa-opioid receptor agonist or prodrug thereof, to a subject in needthereof, sufficient to mitigate said dyskinesia.
 11. The method of claim10, wherein said mu-antagonist or prodrug thereof, and saidkappa-agonist or prodrug thereof are administered together.
 12. A methodof treating or mitigating a dyskinesia, comprising administering atherapeutically effective amount of a prodrug of a dual-action mu-opioidreceptor antagonist/kappa-opioid receptor agonist to a subject in needthereof, sufficient to mitigate said dyskinesia.
 13. The method of claim12 wherein said dual-action mu-antagonist/kappa-agonist is Nalbuphine.14. The method of claim 12 wherein said prodrug is an ester ofNalbuphine, optionally as a pharmaceutically acceptable salt.
 15. Themethod of claim 12 wherein said prodrug is selected from the groupconsisting of the benzoate ester of Nalbuphine, the sebacoyl diester ofNalbuphine, pegylated derivative of Nalbuphine, and pharmaceuticallyacceptable salts thereof.
 16. The method of claim 1, wherein saiddual-action mu-antagonist/kappa-agonist is administered with anotheranti-Parkinson agent.
 17. The method of claim 16, wherein said anotheranti-Parkinson agent is selected from the group consisting of L-DOPA,dopamine agonists, MAO inhibitors, COMT inhibitors, amantadine andanti-cholinergics. 18-24. (canceled)
 25. The method of claim 10, whereinadministration of either of the agents is delayed by 0-12 hrs, andadministration is by the same or a different route.
 26. The method ofclaim 1 wherein said dual-action mu-antagonist/kappa-agonist comprisesNalbuphine administered to a subject via a continuous infusion.
 27. Themethod of claim 26, wherein said continuous infusion dose is at leastabout 0.0001 mg/kg/day.
 28. The method of claim 4, wherein Nalbuphine isadministered orally.
 29. The method of claim 16, wherein said anotheranti-Parkinson agent is L-DOPA.
 30. The method of claim 16, wherein saiddual-action mu-antagonist/kappa-agonist is Nalbuphine or a prodrugthereof, and said another anti-Parkinson agent is L-DOPA.
 31. The methodof claim 16, wherein said another anti-Parkinson agent is a dopamineagonist.
 32. The method of claim 16, wherein said another anti-Parkinsonagent is an MAO inhibitor.
 33. The method of claim 16, wherein saidanother anti-Parkinson agent is a COMT inhibitor.
 34. The method ofclaim 16, wherein said another anti-Parkinson agent is amantadine. 35.The method of claim 16, wherein said another anti-Parkinson agent is ananti-cholinergic.